Beta-amyloid is a product of amyloid precursor protein (APP) processing, which has been implicated in Alzheimer's disease. My currently funded subprojectis studying a number of representative neuroprotective agents to determine which can prevent beta-amyloid aggregation and subsequent beta-amyloid neurotoxic effects in the septal nucleus, a part of the brain which is particularly affected in Alzheimer's disease. The research in mylaboratory utilizesa bilaminar culture system in which neuronal and glial cells from the brain are grown on two separate planes, about a mm apart allowing each to enrich the medium of the other but preventing direct contact. This permits the growth of primary cultures of embryonic septal neurons in the absence of serum, which contains a number of the factors, which I wish to study. My aims are to characterize those factors, which are found to be most promising in the current study with regard to their mechanism of action. It is my hypothesis that beta-amyloid may activate typical apoptotic mechanisms and that neuroprotective factors we have been studying (nerve growth factor (NGF), basic fibroblast growth factor (bFGF), insulin-like growth factors (IGF-I and II), and estrogen may inhibit these mechanisms as seen in some other neurons. The specific aims of the proposed research are: 1) To determine if beta-amyloid or any of the neuroprotective factors alter the number of cells expressing apoptosis related protein, p53, and anti-apoptotic proteins Bcl-2 and p-73 (as measured by immunocytochemistry) or the amounts of the protein (as measured by Western blotting) and 2) To measure the effect of beta-amyloid and neurotrophic factors on activity of enzymes related to apoptosis such as caspase.